(I)Palladium acetate mediated cyclization of ω-unsaturated α-cyano ketones: a new methylenecyclohexane annulation process and its application to the total synthesis of (+)-δ-selinene (II)Total synthesis of (±)-acutifolone A

• Main Authors: Ming-chang Hsieh, 謝閔凔
• Other Authors: Hsing-Jang Liu
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/65965340942035710561

博士 === 國立清華大學 === 化學系 === 95 === Cyclic motifs containing a methylene appendage such as methylenecyclopentane and methylenecyclohexane systems are found in high abundance in naturally occurring compounds, the construction of which typically is a rather involved process. Recently, we developed an annulative approach towards these structurally attractive motifs involving, in the case of methylenecyclopetanes, a highly facile 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2-cycloalkenones followed by a Pd(II)-mediated cyclization of the resulting w-unsaturated a-cyano ketones with concomitant formation of an exocyclic double bond. This 2-step process was found to provide the desired methylenecyclohexanes in good overall yield and further investigation led to the delineation of a process which was catalytic with regards to the expensive palladium reagent. The utility of the annulative process towards the methylenecyclohexane system was demonstrated in the asymmetric total synthesis of the natural product (+)-δ-selinene (123) as well as a project directed towards the asymmetric total synthesis of (+)-10-epijunenol (124). Starting from commercially available l-menthone (147), the requisite a-nitrile was installed via a well precedented 3-step process to yield 146. Conjugate addition of 4-pentenylmagnesium bromide (146à145) followed by the Pd(II) mediated annulation furnished ketone 152. Compound 152 was then treated with lithium naphthalenide to remove the angular nitrile with concomitant transpositioning of the exocyclic olefin to the fully substituted endocyclic position, resulting in the formation of enone 144, the C-6 antipode of neoacolamone (126), a naturally occurring compound. Continuing on towards (+)-d-selinene (123), ketone 144 was reduced with lithium aluminum hydride (144à153) and dehydrated under acidic conditions to achieve the total synthesis of (+)-δ-selinene (123). Towards 10-epijunenol (124), it’s C-7 antipode was synthesized via the reduction of ketone 152, an advanced intermediate generated using a synthetic route similar to that described above with some variations To demonstrate the generality of the abovementioned methodology towards methylenecycloalkanes, the total synthesis of natural product (±)-acutifolone A (192) was also achieved in an efficient manner using the above detailed annulative approach w-unsaturated a-ester ketone 180a as the key step. Starting from commercially available 4-methylcyclohexane (182), ketone 180a was generated via carbomethoxylation, phenylselenenylation followed by oxidative elimination, and Michael addition to afford compound 180a. Pd(II)-mediated cyclization of comound 180a gave the expected methylenecyclopentyl intermediate which was hydrogenated to furnish key itermediate 174. An a,b-unsaturation was installed onto compound 174 via oxidation of its silyl enol ether analogue to furnish enone 191. Michael reaction of compound 191 was then achieved by vinyl magnesium bromide and CuI to afford compound 192, which was oxidized by treatment with Pd(OAc)2 to afford the (±)-acutifolone in racemic form.